Interstitial Chemophototherapy with Light-Activated Nanoparticulate Doxorubicin

光激活纳米颗粒阿霉素间质化学光疗

基本信息

批准号：
10010747
负责人：
GAL SHAFIRSTEIN
金额：
$ 39.99万
依托单位：
POP BIOTECHNOLOGIES, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-06 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010747
关键词：
Address Adverse event Animals Benchmarking Biotechnology Blood Circulation Blood Vessels Buffaloes Cancer Patient Clinic Clinical Research Combination Drug Therapy Comprehensive Cancer Center Computer Models Data Dose Doxorubicin Drug Delivery Systems Drug Kinetics Drug vehicle Effectiveness Elements Encapsulated Formulation Goals Half-Life HepG2 Hour Human In Vitro Lasers Licensing Light Lighting Liposomes Liver neoplasms Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of liver Methods Modeling Mus Nanotechnology National Cancer Institute Neck Oryctolagus cuniculus PUVA Photochemotherapy Patients Pharmaceutical Preparations Pharmacology Phase Phospholipids Phototherapy Porphyrins Pre-Clinical Model Primary Neoplasm Primary carcinoma of the liver cells Property Rattus Rodent Roswell Park Cancer Institute Safety Serum Small Business Technology Transfer Research Survival Rate System Testing Therapeutic Toxic effect Translating Ultrasonography Woodchuck anti-cancer base clinically relevant commercialization dosimetry effective therapy hepatic necrosis image guided improved in vivo interstitial light dosimetry nanoparticulate novel outcome forecast phase 2 study preclinical study primary endpoint response safety testing secondary endpoint subcutaneous success treatment planning tumor tumor ablation tumor growth

项目摘要

SUMMARY Our goal is to advance the commercialization of interstitial chemo-phototherapy (I-CPT) as a potent antitumor therapeutic option for locally advanced tumors. This application will focus on providing a proof of concept for the benefit of I-CPT in the treatment locally advanced hepatocellular carcinoma (HCC). Patients with inoperable locally advanced HCC have a poor prognosis with a 5-year survival rate of just 31%. The combination of chemotherapy and phototherapy (CPT) involves administering a single agent such as PhotoDox, a novel long-circulating, doxorubicin in porphyrin-phospholipid liposome formulation. The major advantages of PhotoDox are: 1) it is thermally independent; 2) has rapid drug release upon 665-nm light administration; 3) is long-circulating (~22 hour half-life), serum stable, and otherwise like DOXIL®; and 4) has been demonstrated to be effective in multiple tumor models. PhotoDox was tested by the National Cancer Institute Nanotechnology Characterization Lab, and was found to be similar to DOXIL® in in vitro toxicity and in vivo pharmacokinetic studies. POP Biotechnologies, Inc. has an exclusive license for PhotoDox. Dr. Shafirstein's team at Roswell Park Cancer Institute (RPCI) has developed and validated a novel system to provide specific light dosimetry in large tumors. In this STTR application, POP Biotechnologies will combine PhotoDox with Dr. Shafirstein’s treatment planning approach to optimize and guide I-CPT for effective therapy of locally advanced liver tumors by accomplishing the following aims: Aim 1: To define light irradiance and fluence for effective I-CPT in subcutaneous HepG2 tumors. The PI validated finite element method approach will be used to guide a light dose finding study to define a safe and effective intratumoral light irradiance and fluence for I-CPT with PhotoDox. We will address the key question: What is the optimal intratumoral light irradiance and fluence for I-CPT with PhotoDox? Aim 2: Demonstrate the effectiveness of I-CPT in an orthotopic liver cancer rat model. We will use the FEM to translate the optimal interstitial light delivery determined in murine tumors (Aim 1) to larger orthotopic liver cancer in rats. We will address the key question: Can we deliver an effective I-CPT with PhotoDox to an orthotopic model of liver tumor? This translational Phase I project will provide required data to guide a Phase II study where our teams will test and study I-CPT with PhotoDox in a spontaneous woodchuck HCC (available at RPCI) that is relevant to understanding I-CPT treatment in the context of human liver cancer patients. If successful, I-CPT with PhotoDox stands to benefit the majority of new liver cancer patients, who have inoperable and problematic primary tumors.

概括我们的目标是推进间质化疗光疗 (I-CPT) 作为一种有效抗肿瘤药物的商业化该应用程序将侧重于为局部晚期肿瘤提供概念证明。 I-CPT 在治疗局部晚期肝细胞癌 (HCC) 患者中的益处。无法手术的局部晚期HCC预后较差，5年生存率仅为31%。化疗和光疗的组合（CPT）涉及使用单一药物，例如 PhotoDox，一种新型长循环阿霉素，采用卟啉-磷脂脂质体制剂。 PhotoDox 的优点是：1) 不受热影响；2) 在 665 nm 光下快速释放药物给药；3) 循环长（半衰期约 22 小时），血清稳定，其他方面与 DOXIL® 相似；4) PhotoDox 已通过国家癌症中心测试研究所纳米技术表征实验室，发现与 DOXIL® 的体外毒性和体内毒性相似体内药代动力学研究。 POP Biotechnologies, Inc. 拥有 Shafirstein 博士团队在罗斯威尔公园的独家许可。癌症研究所 (RPCI) 开发并验证了一种新颖的系统，可在以下情况下提供特定的光剂量测定：在此 STTR 应用中，POP Biotechnologies 将 PhotoDox 与 Shafirstein 博士的技术结合起来。优化和指导 I-CPT 有效治疗局部晚期肝脏肿瘤的治疗计划方法通过实现以下目标：目标 1：定义皮下 HepG2 肿瘤中有效 I-CPT 的光辐照度和注量。 PI 验证的有限元方法将用于指导光剂量发现研究，以定义使用 PhotoDox 进行 I-CPT 的安全有效的瘤内光辐照度和注量我们将解决关键问题。问题：使用 PhotoDox 进行 I-CPT 的最佳瘤内光辐照度和注量是多少？目标 2：证明 I-CPT 在原位肝癌大鼠模型中的有效性。我们将使用 FEM 将小鼠肿瘤中确定的最佳间质光传递（目标 1）转化为我们将解决大鼠更大的原位肝癌的关键问题：我们能否利用 I-CPT 进行有效的治疗？ PhotoDox 用于肝肿瘤原位模型？这个转化性第一阶段项目将提供所需的数据来指导第二阶段研究，我们的团队将在该研究中进行测试并使用 PhotoDox 在自发性土拨鼠 HCC（可在 RPCI 上获得）中研究 I-CPT，这与了解 I-CPT 治疗在人类肝癌患者中的应用如果成功，I-CPT 可以与人类肝癌患者一起使用。 PhotoDox 将使大多数无法手术且有问题的新肝癌患者受益原发性肿瘤。